rs77214077

chrX-154532214-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001360016.2(G6PD):c.1431C>T(p.Pro477=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,209,236 control chromosomes in the GnomAD database, including 161 homozygotes. There are 1,369 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (75 hom., 648 hem., cov: 23)
  • Exomes 𝑓: 0.0025 (86 hom. 721 hem.)
• Consequence: G6PD NM_001360016.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.06

Genes affected

G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-154532214-G-A is Benign according to our data. Variant chrX-154532214-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1431C>T	p.Pro477=	synonymous_variant	12/13	ENST00000393562.10
G6PD	NM_000402.4	c.1521C>T	p.Pro507=	synonymous_variant	12/13
G6PD	NM_001042351.3	c.1431C>T	p.Pro477=	synonymous_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1431C>T	p.Pro477=	synonymous_variant	12/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 2485 AN: 111280 Hom.: 74 Cov.: 23 AF XY: 0.0190 AC XY: 637 AN XY: 33544

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00521

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000189

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00676 AC: 1231 AN: 182188 Hom.: 38 AF XY: 0.00402 AC XY: 270 AN XY: 67082

Gnomad AFR exome AF: 0.0875

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00246 AC: 2702 AN: 1097908 Hom.: 86 Cov.: 37 AF XY: 0.00198 AC XY: 721 AN XY: 363322

Gnomad4 AFR exome AF: 0.0868

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.00506

GnomAD4 genome AF: 0.0224 AC: 2499 AN: 111328 Hom.: 75 Cov.: 23 AF XY: 0.0193 AC XY: 648 AN XY: 33602

Gnomad4 AFR AF: 0.0787

Gnomad4 AMR AF: 0.00521

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000189

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.00461 Hom.: 83

Bravo AF: 0.0263

EpiCase AF: 0.000109

EpiControl AF: 0.000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 10, 2012

- -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

G6PD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

G6PD deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.7
Dann	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77214077; hg19: chrX-153760429;